Phosphoinositide 3-kinases (also called Phosphatidylinositol 3-kinases or PI3Ks) constitute a family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases.
PI3Ks are divided into three different classes: Class I, II and III. Class I PI3Ks are intracellular signal transducer enzymes capable of phosphorylating the phosphatidylinositol-4,5-diphosphate (PIP2) to form the phosphatidylinositol-3,4,5-triphosphate (PIP3). The formation of PIP3 plays a role in the PI3K-dependent activation of the PI3K/AKT/mTOR pathway.
Since PIP3 is restricted to the plasma membrane, it allows the recruitment of AKT and PDK1 (PDK1 or Phosphoinositide-Dependent Protein Kinase 1) to the plasma membrane. The colocalization of activated PDK1 and AKT allows AKT to become phosphorylated by PDK1 on threonine 308, leading to partial activation of AKT. AKT (also known as PKB, Protein Kinase B) is a serine/threonine protein kinase that regulates cellular survival and metabolism by binding and regulating many downstream effectors.
Full activation of AKT occurs upon phosphorylation of serine 473 by the TORC2 complex comprising the mTOR protein kinase (the mammalian target of rapamycin). mTOR is a key protein kinase that regulates cell growth and metabolism to maintain cellular and organismal homeostasis. mTOR is expressed ubiquitously and constitutively. It is found in two complexes: mTOR complexe 1 (mTORC1 or mTOR/raptor) which plays a role in the regulation of translation and cell growth and mTOR complexe 2 (mTORC2 or mTOR/rictor) which regulates several substrates, among them AKT.
The PI3K/AKT/mTOR signaling pathway has been shown to be required for an extremely diverse array of cellular activities, such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The inhibition of the PI3K/AKT/mTOR pathway may thus have a particularly interest in the prevention and/or treatment of benign or malignant tumors, diabetes, age-related disorders, auto-immune disorders and transplant rejection (Don Benjamin et al. Nature Reviews Drug Discovery, 868, November 2011, vol. 10). It has also been shown that PI3K/AKT/mTOR inhibition implements aggregation and activation of death receptors in tumor cells (Beneteau, M. et al. Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway. Molecular cancer research: MCR 6, 604-613, (2008); Pizon, M. et al. Actin-independent exclusion of CD95 by PI3K/AKT signalling: Implications for apoptosis. European journal of immunology 41, (2011)).
Therefore, PI3K/AKT/mTOR inhibitors are a promising target for drug development, in particular in the prevention and/or the treatment of benign and/or malignant tumors. There is thus a need to provide new PI3K/AKT/mTOR inhibitors.